{"gene":"COPS6","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2014,"finding":"CSN6 enhances neddylation of Cullin-1 and facilitates autoubiquitination/degradation of Fbxw7 (a CRL component involved in Myc ubiquitination), thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation, increased Fbxw7 stability, and compromised Myc stability in an Eμ-Myc mouse model, decelerating lymphomagenesis.","method":"Genetic epistasis (Eμ-Myc mouse model with Csn6 haplo-insufficiency), Co-IP, ubiquitination assays, neddylation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, in vivo genetic model with defined phenotypic readout, multiple orthogonal methods in one study","pmids":["25395170"],"is_preprint":false},{"year":2015,"finding":"ERK2 directly binds CSN6 at Leu163/Val165 and phosphorylates CSN6 at Ser148. Phosphorylated CSN6 then inhibits β-Trcp-mediated ubiquitination of β-catenin, stabilizing β-catenin and promoting colorectal cancer development.","method":"Direct binding assay (ERK2-CSN6 interaction), phosphorylation site mutagenesis, ubiquitination assays, Co-IP","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific mutagenesis of phosphorylation sites, direct binding assays, ubiquitination assays, multiple orthogonal methods in a single rigorous study","pmids":["26267535"],"is_preprint":false},{"year":2016,"finding":"CSN6 associates with the E3 ligase CHIP and facilitates CHIP self-ubiquitination and degradation, thereby reducing CHIP-mediated ubiquitination of EGFR and stabilizing EGFR protein levels in glioblastoma cells.","method":"Co-IP, ubiquitination assays, EGFR stability assays (cycloheximide chase), knockdown/overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays in a single lab with two orthogonal methods","pmids":["27546621"],"is_preprint":false},{"year":2015,"finding":"CSN6 interacts with COP1 (E3 ubiquitin ligase) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on nuclear export of p27, which is regulated through COP1's nuclear export signal. COP1 overexpression leads to cytoplasmic distribution of p27, accelerating its degradation.","method":"Co-IP, ubiquitination assay, subcellular fractionation/localization, knockdown/overexpression","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and localization experiment with functional consequence, single lab","pmids":["25945542"],"is_preprint":false},{"year":2015,"finding":"CSN6 associates with MEKK1 and reduces MEKK1 expression by facilitating ubiquitin-mediated degradation of MEKK1. This reduces MEKK1-mediated c-Jun ubiquitination, stabilizing c-Jun and mitigating osmotic stress-mediated c-Jun downregulation.","method":"Co-IP, ubiquitination assay, overexpression/knockdown, osmotic stress treatment","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, single lab, two orthogonal methods","pmids":["26237449"],"is_preprint":false},{"year":2015,"finding":"During DNA damage response, COP1 (regulated by CSN6) is downregulated, compromising COP1's E3 ligase activity toward p27(Kip1) and reducing ubiquitin-mediated degradation of p27. COP1 overexpression downregulates p27 and promotes Aurora A expression, linking the CSN6-COP1-p27-Aurora A axis to genome integrity.","method":"Ubiquitination assay, knockdown/overexpression, western blotting in DNA damage response contexts","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assays and epistasis analysis, single lab","pmids":["25957415"],"is_preprint":false},{"year":2015,"finding":"CSN6 regulates E6AP (UBE3A) stability in cervical cancer: CSN6 associates with E6AP and stabilizes E6AP by reducing its poly-ubiquitination, thereby regulating p53 activity. The CSN6-E6AP axis is regulated by EGF/Akt signaling.","method":"Co-IP, ubiquitination assay, knockdown/overexpression, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays, single lab, two orthogonal methods","pmids":["26318036"],"is_preprint":false},{"year":2012,"finding":"The MPN(-) domain of CSN6 is not required for CSN deneddylase activity, but the C-terminal domain of CSN6 is indispensable for maintaining the integrity of the CSN complex. A CSN assembled with only the C-terminal fragment of Csn6 (lacking the MPN domain) is fully active in cullin deneddylation.","method":"Comparative structural/domain analysis, functional deneddylation assays with domain mutants of mouse Csn6 in yeast and mammalian CSN systems","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain deletion mutagenesis with functional deneddylation reconstitution assay, replicated across yeast and mammalian CSN assemblies","pmids":["22956996"],"is_preprint":false},{"year":2014,"finding":"The MPN domains of CSN5 and CSN6 form a heterodimer; this CSN5/CSN6 association activates the isopeptidase (deneddylase) activity of CSN5, which is otherwise auto-inhibited. However, the CSN5/CSN6 module alone is inefficient in CRL deneddylation, indicating a requirement for other CSN subunits. A hybrid structural model shows that C-termini of CSN subunits likely form a helical bundle scaffolding the complex.","method":"Crystal structure (CSN5/CSN6 MPN domains), isopeptidase activity assay, cross-linking mass spectrometry, cryo-EM docking","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical activity validation and cross-linking MS, multiple orthogonal methods in one study","pmids":["25144743"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the MPN domain from Drosophila CSN6 was solved at 2.5 Å. Structural comparison with other MPN domains shows that CSN6's MPN domain lacks the metal coordination residues required for metalloprotease activity and instead functions as a scaffold.","method":"X-ray crystallography (2.5 Å resolution), structural comparison with other MPN domains, bioinformatics analysis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with structural and bioinformatics validation establishing catalytic incompetence of CSN6 MPN domain","pmids":["22575649"],"is_preprint":false},{"year":2007,"finding":"Nod1 interacts with CSN6 (and other COP9 signalosome components) through its CARD domain. Activation of the Nod1 apoptotic pathway leads to specific cleavage of CSN6, generating a short N-terminal ~3 kDa peptide. This cleavage is blocked by the broad-spectrum caspase inhibitor Z-VAD and by overexpression of CLARP (a caspase-8 inhibitor), implicating caspase-8 in CSN6 processing.","method":"Yeast two-hybrid screening, Co-IP, western blotting with pharmacological caspase inhibitors, overexpression of CLARP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP for interaction, pharmacological and genetic inhibition to define caspase-8 role, single lab","pmids":["17337451"],"is_preprint":false},{"year":2020,"finding":"CSN6 facilitates ubiquitin-mediated degradation of TRIM21 E3 ligase, which decreases TRIM21-mediated OCT1 ubiquitination and stabilizes OCT1. OCT1 stabilization drives ALDH1A1 expression and promotes cancer stemness in colorectal cancer.","method":"Co-IP, ubiquitination assay, organoid formation, limited dilution analysis, in vivo experiments, tissue microarray","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional organoid validation, single lab","pmids":["32225170"],"is_preprint":false},{"year":2021,"finding":"CSN6 stabilizes CDK9 by reducing its ubiquitination levels, thereby activating CDK9-mediated signaling in melanoma. CSN6 associates with and negatively regulates the E3 ligase UBR5, which mediates CDK9 ubiquitination and degradation. UBR5 knockdown abrogated effects caused by CSN6 silencing.","method":"Co-IP, ubiquitination assay, knockdown/rescue experiments, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assays, and epistasis via double-knockdown, single lab","pmids":["33483464"],"is_preprint":false},{"year":2019,"finding":"CSN6 interacts with p16INK4a and the proteasome activator REGγ (PA28γ), facilitating ubiquitin-independent proteasomal degradation of p16 in gastric cancer cells. This promotes gastric cancer cell growth and proliferation.","method":"Co-immunoprecipitation, immunofluorescence localization, ubiquitination assay (demonstrating ubiquitin-independence), xenograft model","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishing ubiquitin-independence, single lab, two orthogonal methods","pmids":["31565481"],"is_preprint":false},{"year":2020,"finding":"The EGFR-ERK pathway upregulates CSN6, which in turn inhibits PD-L1 degradation via the proteasome, stabilizing PD-L1 in glioblastoma cells. CSN6 knockdown decreased PD-L1 expression and increased CHIP expression. ERK blocker PD98059 inhibited CSN6 and PD-L1 upregulation.","method":"siRNA knockdown, EGF stimulation, cycloheximide chase, MG132 proteasome inhibition, western blotting","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic perturbations converging on proteasomal mechanism, single lab","pmids":["32134157"],"is_preprint":false},{"year":2019,"finding":"CSN6 inhibits autophagic degradation of Cathepsin L (CTSL) in cervical cancer cells, thereby promoting migration and invasion. CSN6 inhibits autophagy through the mTOR pathway; blocking mTOR reversed CSN6-mediated autophagy inhibition.","method":"Knockdown/overexpression, autophagy flux assays, mTOR inhibition (rapamycin), migration/invasion assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic epistasis linking CSN6 to mTOR-autophagy-CTSL axis, single lab","pmids":["31223289"],"is_preprint":false},{"year":2023,"finding":"CSN6 inhibits β-Trcp-mediated polyubiquitination and degradation of DDX5, stabilizing DDX5, which in turn promotes DDX5-mediated PHGDH mRNA stabilization. This increases PHGDH expression and upregulates de novo nucleotide biosynthesis (purine and pyrimidine synthesis) in colorectal cancer, contributing to chemoresistance.","method":"Co-IP, ubiquitination assay, isotope metabolite tracing, transcriptomic analysis, Csn6 intestinal conditional knockout mouse model, in vitro/in vivo chemosensitivity assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with isotope tracing, Co-IP, and ubiquitination assays providing multiple orthogonal lines of evidence in single study","pmids":["36512632"],"is_preprint":false},{"year":2024,"finding":"CSN6 antagonizes SPOP ubiquitin ligase to stabilize HMGCS1, which activates YAP1 to promote hepatocellular carcinoma tumor growth. Targeting CSN6 and HMGCS1 hinders tumor growth in orthotopic liver cancer models including high-fat diet conditions.","method":"Co-IP, ubiquitination assay, orthotopic liver cancer model, patient-derived xenograft, knockdown/overexpression","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with in vivo validation, single lab","pmids":["38308184"],"is_preprint":false},{"year":2020,"finding":"CSN6 blocks ubiquitin-proteasome-mediated degradation of Nkx2.2 by interacting with it and inhibiting its ubiquitination, thereby stabilizing Nkx2.2. Nkx2.2 acts as a transcriptional repressor of SIRT2, reducing SIRT2 expression and aggravating cardiac hypertrophy.","method":"Co-IP, ubiquitination assay, overexpression/knockdown in cardiomyocytes, Ang II-induced hypertrophy model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with in vitro and in vivo cardiac hypertrophy model, single lab","pmids":["32882218"],"is_preprint":false},{"year":2020,"finding":"CSN6 stabilizes c-Fos by binding to it and decreasing its ubiquitination in pancreatic adenocarcinoma cells. Stabilized c-Fos promotes FOXA1 expression, which drives invasion and metastasis.","method":"Co-IP, ubiquitination assay, knockdown/rescue experiments","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, no structural validation","pmids":["32289284"],"is_preprint":false},{"year":2020,"finding":"CSN6 associates with Snail1 and enhances Snail1 protein stability by inhibiting ubiquitin-mediated degradation of Snail1, thereby promoting breast cancer cell migration.","method":"Co-IP, ubiquitination assay, migration assay, xenograft experiment","journal":"International journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab","pmids":["33162808"],"is_preprint":false},{"year":2018,"finding":"CSN6 positively regulates β-catenin expression in a β-Trcp-dependent manner in papillary thyroid cancer cells, stabilizing β-catenin and facilitating EMT. CSN6 silencing sensitized PTC cells to FH535 via Wnt/β-catenin pathway downregulation.","method":"Western blotting, knockdown, in vitro/in vivo proliferation and migration assays","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway analysis by western blot and phenotypic assays without direct Co-IP or ubiquitination assay for CSN6-β-Trcp interaction in this study","pmids":["29341469"],"is_preprint":false},{"year":2018,"finding":"CSN6 regulates androgen receptor (AR) transport in mouse testicular Sertoli cells through phosphorylation signaling. CSN6 was identified by mass spectrometry as an AR-interacting protein, verified by Co-IP, and its knockdown disrupted testosterone-induced cytoplasmic AR translocation to the plasma membrane.","method":"Mass spectrometry, Co-IP, western blot, shRNA knockdown","journal":"Cellular physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP confirmation after MS screen, single lab, limited mechanistic follow-up","pmids":["29991022"],"is_preprint":false},{"year":2025,"finding":"CSN6 antagonizes DCAF1-mediated ubiquitination of NPM1 by interacting with DCAF1, thereby stabilizing NPM1 and promoting NPM1-orchestrated ribosome biogenesis and translation of gemcitabine resistance genes (CDA, RRM1/2) in pancreatic ductal adenocarcinoma. Conditional KO of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model.","method":"Co-IP, proteomic analysis, conditional knockout mouse model (KPP spontaneous PDAC), ubiquitination assay, xenograft","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model, proteomic analysis, Co-IP, and ubiquitination assays with multiple orthogonal methods and in vivo validation in single study","pmids":["41114465"],"is_preprint":false},{"year":2011,"finding":"In zebrafish, cops6 knockdown disrupts dorsoventral patterning, convergent extension movement, brain formation, and promotes apoptosis during segmentation, establishing cops6 as playing anti-apoptotic and developmental roles during early embryogenesis.","method":"Morpholino knockdown in zebrafish embryos, phenotypic analysis of developmental processes","journal":"The International journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined loss-of-function with multiple specific phenotypic readouts in a vertebrate model organism, single lab","pmids":["21425078"],"is_preprint":false},{"year":2023,"finding":"ALDOA (aldolase A) binds COPS6 (identified by immunoprecipitation and mass spectrometry), and COPS6 depletion inhibited the promoting effects of ALDOA on CRC cell proliferation and metastasis, placing COPS6 downstream of ALDOA in the MAPK/EMT-activating pathway.","method":"Immunoprecipitation, mass spectrometry, epistasis via COPS6 knockdown in ALDOA-overexpressing cells","journal":"Disease markers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification with genetic epistasis, single lab, limited mechanistic follow-up on CSN6 mechanism","pmids":["37457886"],"is_preprint":false},{"year":2023,"finding":"p53 negatively regulates COPS6 promoter activity in osteosarcoma (U2OS) and lung cancer (H1299) cells, placing COPS6 downstream of p53 transcriptional regulation.","method":"Promoter activity (luciferase) assay, p53 overexpression/knockdown","journal":"Acta pharmacologica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single promoter reporter assay, single lab","pmids":["37095198"],"is_preprint":false}],"current_model":"COPS6/CSN6 is a non-catalytic MPN-domain subunit of the COP9 signalosome whose C-terminal domain scaffolds the complex while its MPN domain activates the catalytic CSN5 isopeptidase; it acts as a broad regulator of the ubiquitin-proteasome system by binding to and promoting autoubiquitination/degradation of multiple E3 ubiquitin ligases (CHIP, Fbxw7, MEKK1, TRIM21, UBR5, SPOP, DCAF1, COP1, E6AP), thereby stabilizing their substrates (EGFR, Myc, c-Jun, β-catenin, CDK9, HMGCS1, NPM1, OCT1, p27, Snail1, c-Fos, Nkx2.2, p16); CSN6 is phosphorylated by ERK2 at Ser148 (binding at Leu163/Val165), and is cleaved by caspase-8 during apoptosis, and its overexpression drives oncogenic metabolic reprogramming, cancer stemness, and immune evasion across multiple cancer types."},"narrative":{"mechanistic_narrative":"COPS6/CSN6 is a non-catalytic MPN-domain subunit of the COP9 signalosome that functions as a broad regulator of the ubiquitin-proteasome system and a driver of oncogenic protein stabilization [PMID:25395170, PMID:25144743]. Structurally, its MPN domain lacks the metal-coordination residues needed for metalloprotease activity and instead heterodimerizes with the MPN domain of CSN5 to relieve CSN5 autoinhibition and activate the complex's isopeptidase (deneddylase) activity, while its C-terminal domain is indispensable for assembly and integrity of the CSN complex [PMID:22956996, PMID:25144743, PMID:22575649]. Through these activities CSN6 modulates cullin-RING ligase function, enhancing Cullin-1 neddylation [PMID:25395170]. Beyond the core complex, CSN6 governs the stability of numerous E3 ubiquitin ligases: it promotes the autoubiquitination/degradation of Fbxw7, CHIP, MEKK1, TRIM21, UBR5, SPOP, and DCAF1, and conversely stabilizes E6AP, thereby controlling the abundance of their downstream substrates including Myc, EGFR, c-Jun, OCT1, CDK9, HMGCS1, and NPM1 [PMID:25395170, PMID:27546621, PMID:26237449, PMID:32225170, PMID:33483464, PMID:38308184, PMID:41114465]. It also acts through β-TrCP-dependent routes to stabilize β-catenin and DDX5 [PMID:26267535, PMID:36512632] and is integrated into signaling: ERK2 directly binds CSN6 at Leu163/Val165 and phosphorylates it at Ser148, enabling β-catenin stabilization in colorectal cancer [PMID:26267535]. The net consequence of CSN6 overexpression is stabilization of oncoproteins, metabolic reprogramming toward nucleotide biosynthesis, cancer stemness, chemoresistance, and immune evasion via PD-L1 stabilization across multiple tumor types [PMID:32134157, PMID:36512632, PMID:41114465]. CSN6 is also a caspase-8 substrate during Nod1-driven apoptosis [PMID:17337451], and in zebrafish cops6 is required for dorsoventral patterning, convergent extension, and embryonic survival [PMID:21425078].","teleology":[{"year":2007,"claim":"Established CSN6 as a target of apoptotic proteolysis, linking it to innate-immune/apoptotic signaling through Nod1.","evidence":"Yeast two-hybrid and Co-IP with Nod1, plus caspase inhibitor and CLARP overexpression in cells","pmids":["17337451"],"confidence":"Medium","gaps":["Functional consequence of CSN6 cleavage on CSN activity not defined","Direct caspase-8 cleavage site not mapped"]},{"year":2011,"claim":"Showed CSN6 has an essential anti-apoptotic and developmental role in a whole vertebrate, beyond cultured cancer cells.","evidence":"Morpholino knockdown of cops6 in zebrafish embryos with phenotypic analysis","pmids":["21425078"],"confidence":"Medium","gaps":["Molecular pathway mediating developmental phenotypes not identified","Morpholino specificity not genetically confirmed"]},{"year":2012,"claim":"Resolved why CSN6 is non-catalytic and what its domains do, establishing the MPN domain as a scaffold and the C-terminus as the assembly determinant.","evidence":"X-ray crystallography of Drosophila CSN6 MPN domain and domain-deletion deneddylation reconstitution in yeast and mammalian CSN","pmids":["22575649","22956996"],"confidence":"High","gaps":["Full-length CSN6 structure within the holo-complex not resolved in these studies","Role of MPN domain in non-CSN functions unaddressed"]},{"year":2014,"claim":"Defined how the CSN5/CSN6 MPN heterodimer activates catalysis and connected CSN6 to cullin neddylation and oncoprotein control in vivo.","evidence":"Crystal structure of CSN5/CSN6 MPN dimer with isopeptidase assays; Eµ-Myc mouse with Csn6 haploinsufficiency, Co-IP, ubiquitination and neddylation assays","pmids":["25144743","25395170"],"confidence":"High","gaps":["CSN5/CSN6 module alone is inefficient on CRLs, requiring other subunits not fully defined","Direct vs. indirect basis of CSN6 enhancing Cullin-1 neddylation not separated"]},{"year":2015,"claim":"Embedded CSN6 in growth-factor signaling and broadened its E3-ligase regulatory repertoire, revealing a recurring 'degrade-the-ligase' or 'stabilize-the-ligase' logic that controls substrate abundance.","evidence":"ERK2-CSN6 direct binding and Ser148 phosphorylation mutagenesis; Co-IP and ubiquitination assays for CHIP/EGFR, COP1/p27, MEKK1/c-Jun, E6AP/p53 axes","pmids":["26267535","27546621","25945542","26237449","25957415","26318036"],"confidence":"High","gaps":["Whether these effects require the holo-CSN complex or free CSN6 is unclear","Most ligase axes shown in single labs without reciprocal cross-validation"]},{"year":2023,"claim":"Connected CSN6 to metabolic reprogramming and chemoresistance through genetic in vivo models, moving beyond correlative cancer-cell observations.","evidence":"Intestinal conditional Csn6 KO mouse with isotope metabolite tracing, Co-IP and ubiquitination assays (β-TrCP/DDX5/PHGDH axis)","pmids":["36512632"],"confidence":"High","gaps":["Mechanism by which CSN6 selects β-TrCP substrates not defined","Generalizability of nucleotide-biosynthesis axis to other tumors untested here"]},{"year":2025,"claim":"Demonstrated CSN6-driven ribosome biogenesis and gemcitabine resistance via DCAF1/NPM1, with a spontaneous-tumor genetic requirement.","evidence":"Co-IP, proteomics, ubiquitination assays, and conditional CSN6 KO in a KPP spontaneous PDAC mouse model","pmids":["41114465"],"confidence":"High","gaps":["Structural basis of CSN6-DCAF1 interaction not defined","Whether NPM1 stabilization depends on CSN deneddylase activity unresolved"]},{"year":null,"claim":"It remains unresolved which CSN6 functions require the intact COP9 signalosome versus free or sub-complexed CSN6, and how CSN6 achieves selectivity among its many E3-ligase partners and substrates.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CSN6 bound to any of its E3-ligase partners","Determinants of substrate/ligase selectivity unknown","Relationship between deneddylase activity and ligase-stability control not mechanistically linked"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,4,11,12,16,17,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,13]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,8,16,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[24]}],"complexes":["COP9 signalosome"],"partners":["COPS5","ERK2","COP1","CHIP","TRIM21","UBR5","DCAF1","SPOP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L5N1","full_name":"COP9 signalosome complex subunit 6","aliases":["JAB1-containing signalosome subunit 6","MOV34 homolog","Vpr-interacting protein","hVIP"],"length_aa":327,"mass_kda":36.2,"function":"Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Has some glucocorticoid receptor-responsive activity. Stabilizes COP1 through reducing COP1 auto-ubiquitination and decelerating COP1 turnover rate, hence regulates the ubiquitination of COP1 targets","subcellular_location":"Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q7L5N1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/COPS6","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDB1","stoichiometry":4.0},{"gene":"AGO2","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"WDR3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COPS6","total_profiled":1310},"omim":[{"mim_id":"619349","title":"COP9 SIGNALOSOME, SUBUNIT 9; COPS9","url":"https://www.omim.org/entry/619349"},{"mim_id":"616008","title":"COP9 SIGNALOSOME, SUBUNIT 4; COPS4","url":"https://www.omim.org/entry/616008"},{"mim_id":"614729","title":"COP9 SIGNALOSOME, SUBUNIT 6; COPS6","url":"https://www.omim.org/entry/614729"},{"mim_id":"608067","title":"RING FINGER AND WD REPEAT DOMAINS-CONTAINING PROTEIN 2; RFWD2","url":"https://www.omim.org/entry/608067"},{"mim_id":"604850","title":"COP9 SIGNALOSOME, SUBUNIT 5; COPS5","url":"https://www.omim.org/entry/604850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COPS6"},"hgnc":{"alias_symbol":["MOV34-34KD","CSN6"],"prev_symbol":[]},"alphafold":{"accession":"Q7L5N1","domains":[{"cath_id":"3.40.140.10","chopping":"39-193","consensus_level":"high","plddt":94.7246,"start":39,"end":193},{"cath_id":"1.10.287","chopping":"218-278","consensus_level":"medium","plddt":89.6011,"start":218,"end":278}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L5N1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L5N1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L5N1-F1-predicted_aligned_error_v6.png","plddt_mean":84.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COPS6","jax_strain_url":"https://www.jax.org/strain/search?query=COPS6"},"sequence":{"accession":"Q7L5N1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L5N1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L5N1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L5N1"}},"corpus_meta":[{"pmid":"27546621","id":"PMC_27546621","title":"CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27546621","citation_count":84,"is_preprint":false},{"pmid":"27748879","id":"PMC_27748879","title":"Quercetin-induced apoptosis of HT-29 colon cancer cells via inhibition of the Akt-CSN6-Myc signaling axis.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27748879","citation_count":69,"is_preprint":false},{"pmid":"26267535","id":"PMC_26267535","title":"ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development.","date":"2015","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/26267535","citation_count":68,"is_preprint":false},{"pmid":"25395170","id":"PMC_25395170","title":"CSN6 drives carcinogenesis by positively regulating Myc stability.","date":"2014","source":"Nature 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Csn6 haplo-insufficiency decreased Cullin-1 neddylation, increased Fbxw7 stability, and compromised Myc stability in an Eμ-Myc mouse model, decelerating lymphomagenesis.\",\n      \"method\": \"Genetic epistasis (Eμ-Myc mouse model with Csn6 haplo-insufficiency), Co-IP, ubiquitination assays, neddylation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, in vivo genetic model with defined phenotypic readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25395170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERK2 directly binds CSN6 at Leu163/Val165 and phosphorylates CSN6 at Ser148. Phosphorylated CSN6 then inhibits β-Trcp-mediated ubiquitination of β-catenin, stabilizing β-catenin and promoting colorectal cancer development.\",\n      \"method\": \"Direct binding assay (ERK2-CSN6 interaction), phosphorylation site mutagenesis, ubiquitination assays, Co-IP\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific mutagenesis of phosphorylation sites, direct binding assays, ubiquitination assays, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26267535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CSN6 associates with the E3 ligase CHIP and facilitates CHIP self-ubiquitination and degradation, thereby reducing CHIP-mediated ubiquitination of EGFR and stabilizing EGFR protein levels in glioblastoma cells.\",\n      \"method\": \"Co-IP, ubiquitination assays, EGFR stability assays (cycloheximide chase), knockdown/overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays in a single lab with two orthogonal methods\",\n      \"pmids\": [\"27546621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CSN6 interacts with COP1 (E3 ubiquitin ligase) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on nuclear export of p27, which is regulated through COP1's nuclear export signal. COP1 overexpression leads to cytoplasmic distribution of p27, accelerating its degradation.\",\n      \"method\": \"Co-IP, ubiquitination assay, subcellular fractionation/localization, knockdown/overexpression\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and localization experiment with functional consequence, single lab\",\n      \"pmids\": [\"25945542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CSN6 associates with MEKK1 and reduces MEKK1 expression by facilitating ubiquitin-mediated degradation of MEKK1. This reduces MEKK1-mediated c-Jun ubiquitination, stabilizing c-Jun and mitigating osmotic stress-mediated c-Jun downregulation.\",\n      \"method\": \"Co-IP, ubiquitination assay, overexpression/knockdown, osmotic stress treatment\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"26237449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During DNA damage response, COP1 (regulated by CSN6) is downregulated, compromising COP1's E3 ligase activity toward p27(Kip1) and reducing ubiquitin-mediated degradation of p27. COP1 overexpression downregulates p27 and promotes Aurora A expression, linking the CSN6-COP1-p27-Aurora A axis to genome integrity.\",\n      \"method\": \"Ubiquitination assay, knockdown/overexpression, western blotting in DNA damage response contexts\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assays and epistasis analysis, single lab\",\n      \"pmids\": [\"25957415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CSN6 regulates E6AP (UBE3A) stability in cervical cancer: CSN6 associates with E6AP and stabilizes E6AP by reducing its poly-ubiquitination, thereby regulating p53 activity. The CSN6-E6AP axis is regulated by EGF/Akt signaling.\",\n      \"method\": \"Co-IP, ubiquitination assay, knockdown/overexpression, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"26318036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The MPN(-) domain of CSN6 is not required for CSN deneddylase activity, but the C-terminal domain of CSN6 is indispensable for maintaining the integrity of the CSN complex. A CSN assembled with only the C-terminal fragment of Csn6 (lacking the MPN domain) is fully active in cullin deneddylation.\",\n      \"method\": \"Comparative structural/domain analysis, functional deneddylation assays with domain mutants of mouse Csn6 in yeast and mammalian CSN systems\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain deletion mutagenesis with functional deneddylation reconstitution assay, replicated across yeast and mammalian CSN assemblies\",\n      \"pmids\": [\"22956996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The MPN domains of CSN5 and CSN6 form a heterodimer; this CSN5/CSN6 association activates the isopeptidase (deneddylase) activity of CSN5, which is otherwise auto-inhibited. However, the CSN5/CSN6 module alone is inefficient in CRL deneddylation, indicating a requirement for other CSN subunits. A hybrid structural model shows that C-termini of CSN subunits likely form a helical bundle scaffolding the complex.\",\n      \"method\": \"Crystal structure (CSN5/CSN6 MPN domains), isopeptidase activity assay, cross-linking mass spectrometry, cryo-EM docking\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical activity validation and cross-linking MS, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25144743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the MPN domain from Drosophila CSN6 was solved at 2.5 Å. Structural comparison with other MPN domains shows that CSN6's MPN domain lacks the metal coordination residues required for metalloprotease activity and instead functions as a scaffold.\",\n      \"method\": \"X-ray crystallography (2.5 Å resolution), structural comparison with other MPN domains, bioinformatics analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with structural and bioinformatics validation establishing catalytic incompetence of CSN6 MPN domain\",\n      \"pmids\": [\"22575649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nod1 interacts with CSN6 (and other COP9 signalosome components) through its CARD domain. Activation of the Nod1 apoptotic pathway leads to specific cleavage of CSN6, generating a short N-terminal ~3 kDa peptide. This cleavage is blocked by the broad-spectrum caspase inhibitor Z-VAD and by overexpression of CLARP (a caspase-8 inhibitor), implicating caspase-8 in CSN6 processing.\",\n      \"method\": \"Yeast two-hybrid screening, Co-IP, western blotting with pharmacological caspase inhibitors, overexpression of CLARP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP for interaction, pharmacological and genetic inhibition to define caspase-8 role, single lab\",\n      \"pmids\": [\"17337451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSN6 facilitates ubiquitin-mediated degradation of TRIM21 E3 ligase, which decreases TRIM21-mediated OCT1 ubiquitination and stabilizes OCT1. OCT1 stabilization drives ALDH1A1 expression and promotes cancer stemness in colorectal cancer.\",\n      \"method\": \"Co-IP, ubiquitination assay, organoid formation, limited dilution analysis, in vivo experiments, tissue microarray\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with functional organoid validation, single lab\",\n      \"pmids\": [\"32225170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CSN6 stabilizes CDK9 by reducing its ubiquitination levels, thereby activating CDK9-mediated signaling in melanoma. CSN6 associates with and negatively regulates the E3 ligase UBR5, which mediates CDK9 ubiquitination and degradation. UBR5 knockdown abrogated effects caused by CSN6 silencing.\",\n      \"method\": \"Co-IP, ubiquitination assay, knockdown/rescue experiments, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assays, and epistasis via double-knockdown, single lab\",\n      \"pmids\": [\"33483464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSN6 interacts with p16INK4a and the proteasome activator REGγ (PA28γ), facilitating ubiquitin-independent proteasomal degradation of p16 in gastric cancer cells. This promotes gastric cancer cell growth and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, ubiquitination assay (demonstrating ubiquitin-independence), xenograft model\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay establishing ubiquitin-independence, single lab, two orthogonal methods\",\n      \"pmids\": [\"31565481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The EGFR-ERK pathway upregulates CSN6, which in turn inhibits PD-L1 degradation via the proteasome, stabilizing PD-L1 in glioblastoma cells. CSN6 knockdown decreased PD-L1 expression and increased CHIP expression. ERK blocker PD98059 inhibited CSN6 and PD-L1 upregulation.\",\n      \"method\": \"siRNA knockdown, EGF stimulation, cycloheximide chase, MG132 proteasome inhibition, western blotting\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic perturbations converging on proteasomal mechanism, single lab\",\n      \"pmids\": [\"32134157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSN6 inhibits autophagic degradation of Cathepsin L (CTSL) in cervical cancer cells, thereby promoting migration and invasion. CSN6 inhibits autophagy through the mTOR pathway; blocking mTOR reversed CSN6-mediated autophagy inhibition.\",\n      \"method\": \"Knockdown/overexpression, autophagy flux assays, mTOR inhibition (rapamycin), migration/invasion assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic epistasis linking CSN6 to mTOR-autophagy-CTSL axis, single lab\",\n      \"pmids\": [\"31223289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CSN6 inhibits β-Trcp-mediated polyubiquitination and degradation of DDX5, stabilizing DDX5, which in turn promotes DDX5-mediated PHGDH mRNA stabilization. This increases PHGDH expression and upregulates de novo nucleotide biosynthesis (purine and pyrimidine synthesis) in colorectal cancer, contributing to chemoresistance.\",\n      \"method\": \"Co-IP, ubiquitination assay, isotope metabolite tracing, transcriptomic analysis, Csn6 intestinal conditional knockout mouse model, in vitro/in vivo chemosensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with isotope tracing, Co-IP, and ubiquitination assays providing multiple orthogonal lines of evidence in single study\",\n      \"pmids\": [\"36512632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CSN6 antagonizes SPOP ubiquitin ligase to stabilize HMGCS1, which activates YAP1 to promote hepatocellular carcinoma tumor growth. Targeting CSN6 and HMGCS1 hinders tumor growth in orthotopic liver cancer models including high-fat diet conditions.\",\n      \"method\": \"Co-IP, ubiquitination assay, orthotopic liver cancer model, patient-derived xenograft, knockdown/overexpression\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with in vivo validation, single lab\",\n      \"pmids\": [\"38308184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSN6 blocks ubiquitin-proteasome-mediated degradation of Nkx2.2 by interacting with it and inhibiting its ubiquitination, thereby stabilizing Nkx2.2. Nkx2.2 acts as a transcriptional repressor of SIRT2, reducing SIRT2 expression and aggravating cardiac hypertrophy.\",\n      \"method\": \"Co-IP, ubiquitination assay, overexpression/knockdown in cardiomyocytes, Ang II-induced hypertrophy model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with in vitro and in vivo cardiac hypertrophy model, single lab\",\n      \"pmids\": [\"32882218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSN6 stabilizes c-Fos by binding to it and decreasing its ubiquitination in pancreatic adenocarcinoma cells. Stabilized c-Fos promotes FOXA1 expression, which drives invasion and metastasis.\",\n      \"method\": \"Co-IP, ubiquitination assay, knockdown/rescue experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab, no structural validation\",\n      \"pmids\": [\"32289284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSN6 associates with Snail1 and enhances Snail1 protein stability by inhibiting ubiquitin-mediated degradation of Snail1, thereby promoting breast cancer cell migration.\",\n      \"method\": \"Co-IP, ubiquitination assay, migration assay, xenograft experiment\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"33162808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSN6 positively regulates β-catenin expression in a β-Trcp-dependent manner in papillary thyroid cancer cells, stabilizing β-catenin and facilitating EMT. CSN6 silencing sensitized PTC cells to FH535 via Wnt/β-catenin pathway downregulation.\",\n      \"method\": \"Western blotting, knockdown, in vitro/in vivo proliferation and migration assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway analysis by western blot and phenotypic assays without direct Co-IP or ubiquitination assay for CSN6-β-Trcp interaction in this study\",\n      \"pmids\": [\"29341469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSN6 regulates androgen receptor (AR) transport in mouse testicular Sertoli cells through phosphorylation signaling. CSN6 was identified by mass spectrometry as an AR-interacting protein, verified by Co-IP, and its knockdown disrupted testosterone-induced cytoplasmic AR translocation to the plasma membrane.\",\n      \"method\": \"Mass spectrometry, Co-IP, western blot, shRNA knockdown\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirmation after MS screen, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"29991022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CSN6 antagonizes DCAF1-mediated ubiquitination of NPM1 by interacting with DCAF1, thereby stabilizing NPM1 and promoting NPM1-orchestrated ribosome biogenesis and translation of gemcitabine resistance genes (CDA, RRM1/2) in pancreatic ductal adenocarcinoma. Conditional KO of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model.\",\n      \"method\": \"Co-IP, proteomic analysis, conditional knockout mouse model (KPP spontaneous PDAC), ubiquitination assay, xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model, proteomic analysis, Co-IP, and ubiquitination assays with multiple orthogonal methods and in vivo validation in single study\",\n      \"pmids\": [\"41114465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish, cops6 knockdown disrupts dorsoventral patterning, convergent extension movement, brain formation, and promotes apoptosis during segmentation, establishing cops6 as playing anti-apoptotic and developmental roles during early embryogenesis.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos, phenotypic analysis of developmental processes\",\n      \"journal\": \"The International journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined loss-of-function with multiple specific phenotypic readouts in a vertebrate model organism, single lab\",\n      \"pmids\": [\"21425078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOA (aldolase A) binds COPS6 (identified by immunoprecipitation and mass spectrometry), and COPS6 depletion inhibited the promoting effects of ALDOA on CRC cell proliferation and metastasis, placing COPS6 downstream of ALDOA in the MAPK/EMT-activating pathway.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, epistasis via COPS6 knockdown in ALDOA-overexpressing cells\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification with genetic epistasis, single lab, limited mechanistic follow-up on CSN6 mechanism\",\n      \"pmids\": [\"37457886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p53 negatively regulates COPS6 promoter activity in osteosarcoma (U2OS) and lung cancer (H1299) cells, placing COPS6 downstream of p53 transcriptional regulation.\",\n      \"method\": \"Promoter activity (luciferase) assay, p53 overexpression/knockdown\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single promoter reporter assay, single lab\",\n      \"pmids\": [\"37095198\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COPS6/CSN6 is a non-catalytic MPN-domain subunit of the COP9 signalosome whose C-terminal domain scaffolds the complex while its MPN domain activates the catalytic CSN5 isopeptidase; it acts as a broad regulator of the ubiquitin-proteasome system by binding to and promoting autoubiquitination/degradation of multiple E3 ubiquitin ligases (CHIP, Fbxw7, MEKK1, TRIM21, UBR5, SPOP, DCAF1, COP1, E6AP), thereby stabilizing their substrates (EGFR, Myc, c-Jun, β-catenin, CDK9, HMGCS1, NPM1, OCT1, p27, Snail1, c-Fos, Nkx2.2, p16); CSN6 is phosphorylated by ERK2 at Ser148 (binding at Leu163/Val165), and is cleaved by caspase-8 during apoptosis, and its overexpression drives oncogenic metabolic reprogramming, cancer stemness, and immune evasion across multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COPS6/CSN6 is a non-catalytic MPN-domain subunit of the COP9 signalosome that functions as a broad regulator of the ubiquitin-proteasome system and a driver of oncogenic protein stabilization [#0, #8]. Structurally, its MPN domain lacks the metal-coordination residues needed for metalloprotease activity and instead heterodimerizes with the MPN domain of CSN5 to relieve CSN5 autoinhibition and activate the complex's isopeptidase (deneddylase) activity, while its C-terminal domain is indispensable for assembly and integrity of the CSN complex [#7, #8, #9]. Through these activities CSN6 modulates cullin-RING ligase function, enhancing Cullin-1 neddylation [#0]. Beyond the core complex, CSN6 governs the stability of numerous E3 ubiquitin ligases: it promotes the autoubiquitination/degradation of Fbxw7, CHIP, MEKK1, TRIM21, UBR5, SPOP, and DCAF1, and conversely stabilizes E6AP, thereby controlling the abundance of their downstream substrates including Myc, EGFR, c-Jun, OCT1, CDK9, HMGCS1, and NPM1 [#0, #2, #4, #11, #12, #17, #23]. It also acts through β-TrCP-dependent routes to stabilize β-catenin and DDX5 [#1, #16] and is integrated into signaling: ERK2 directly binds CSN6 at Leu163/Val165 and phosphorylates it at Ser148, enabling β-catenin stabilization in colorectal cancer [#1]. The net consequence of CSN6 overexpression is stabilization of oncoproteins, metabolic reprogramming toward nucleotide biosynthesis, cancer stemness, chemoresistance, and immune evasion via PD-L1 stabilization across multiple tumor types [#14, #16, #23]. CSN6 is also a caspase-8 substrate during Nod1-driven apoptosis [#10], and in zebrafish cops6 is required for dorsoventral patterning, convergent extension, and embryonic survival [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established CSN6 as a target of apoptotic proteolysis, linking it to innate-immune/apoptotic signaling through Nod1.\",\n      \"evidence\": \"Yeast two-hybrid and Co-IP with Nod1, plus caspase inhibitor and CLARP overexpression in cells\",\n      \"pmids\": [\"17337451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CSN6 cleavage on CSN activity not defined\", \"Direct caspase-8 cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CSN6 has an essential anti-apoptotic and developmental role in a whole vertebrate, beyond cultured cancer cells.\",\n      \"evidence\": \"Morpholino knockdown of cops6 in zebrafish embryos with phenotypic analysis\",\n      \"pmids\": [\"21425078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway mediating developmental phenotypes not identified\", \"Morpholino specificity not genetically confirmed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved why CSN6 is non-catalytic and what its domains do, establishing the MPN domain as a scaffold and the C-terminus as the assembly determinant.\",\n      \"evidence\": \"X-ray crystallography of Drosophila CSN6 MPN domain and domain-deletion deneddylation reconstitution in yeast and mammalian CSN\",\n      \"pmids\": [\"22575649\", \"22956996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length CSN6 structure within the holo-complex not resolved in these studies\", \"Role of MPN domain in non-CSN functions unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined how the CSN5/CSN6 MPN heterodimer activates catalysis and connected CSN6 to cullin neddylation and oncoprotein control in vivo.\",\n      \"evidence\": \"Crystal structure of CSN5/CSN6 MPN dimer with isopeptidase assays; Eµ-Myc mouse with Csn6 haploinsufficiency, Co-IP, ubiquitination and neddylation assays\",\n      \"pmids\": [\"25144743\", \"25395170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CSN5/CSN6 module alone is inefficient on CRLs, requiring other subunits not fully defined\", \"Direct vs. indirect basis of CSN6 enhancing Cullin-1 neddylation not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Embedded CSN6 in growth-factor signaling and broadened its E3-ligase regulatory repertoire, revealing a recurring 'degrade-the-ligase' or 'stabilize-the-ligase' logic that controls substrate abundance.\",\n      \"evidence\": \"ERK2-CSN6 direct binding and Ser148 phosphorylation mutagenesis; Co-IP and ubiquitination assays for CHIP/EGFR, COP1/p27, MEKK1/c-Jun, E6AP/p53 axes\",\n      \"pmids\": [\"26267535\", \"27546621\", \"25945542\", \"26237449\", \"25957415\", \"26318036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these effects require the holo-CSN complex or free CSN6 is unclear\", \"Most ligase axes shown in single labs without reciprocal cross-validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected CSN6 to metabolic reprogramming and chemoresistance through genetic in vivo models, moving beyond correlative cancer-cell observations.\",\n      \"evidence\": \"Intestinal conditional Csn6 KO mouse with isotope metabolite tracing, Co-IP and ubiquitination assays (β-TrCP/DDX5/PHGDH axis)\",\n      \"pmids\": [\"36512632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CSN6 selects β-TrCP substrates not defined\", \"Generalizability of nucleotide-biosynthesis axis to other tumors untested here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated CSN6-driven ribosome biogenesis and gemcitabine resistance via DCAF1/NPM1, with a spontaneous-tumor genetic requirement.\",\n      \"evidence\": \"Co-IP, proteomics, ubiquitination assays, and conditional CSN6 KO in a KPP spontaneous PDAC mouse model\",\n      \"pmids\": [\"41114465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CSN6-DCAF1 interaction not defined\", \"Whether NPM1 stabilization depends on CSN deneddylase activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which CSN6 functions require the intact COP9 signalosome versus free or sub-complexed CSN6, and how CSN6 achieves selectivity among its many E3-ligase partners and substrates.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CSN6 bound to any of its E3-ligase partners\", \"Determinants of substrate/ligase selectivity unknown\", \"Relationship between deneddylase activity and ligase-stability control not mechanistically linked\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 4, 11, 12, 16, 17, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 8, 16, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"complexes\": [\"COP9 signalosome\"],\n    \"partners\": [\"COPS5\", \"ERK2\", \"COP1\", \"CHIP\", \"TRIM21\", \"UBR5\", \"DCAF1\", \"SPOP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}